The unifying thread of the research proposed in this application is the development of stereo- and enantiocontrolled methods for constructing all-carbon quaternary carbon centers. Although notable progress has been achieved in this area, the construction of chiral, all-carbon quaternary centers remains a major hurdle for chemical synthesis, or modification, of numerous biologically significant molecules. The proposed studies will further define the utility of two powerful methods that we have pioneered for assembling complex skeleta containing quaternary carbon centers: intramolecular Heck insertions and alkylations of prochiral enolates with chiral sp3 electrophiles. Complex alkaloids that contain multiple pyrrolidinoindoline subunits are a major focus of our proposed total synthesis endeavors. Our aim here is to develop general methods and synthesis strategies that, for the first time, will allow pharmacologically significant members of this large indole alkaloid family to be accessed on meaningful scales by chemical synthesis. Polyindoline alkaloid total synthesis targets include hodgkinsine, idiospermuline, quadrigemines A, C and H, communesin A, and 11,11'- dideoxyverticillin. Other total synthesis targets are vincorine and vincorine-related alkaloid libraries and the complex cardenolides ouabain, strophanthidin and sarmentosigenin A. We will also collaborate in studies to define the structural basis of the analgesic activity of polyindoline alkaloids and evaluate the antiinfective and antitumor properties of representative polyindoline alkaloids.